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New drug has some success in rheumatoid arthritis

A new drug (sirukumab) is a promising treatment option for refractory rheumatoid arthritis patients, found multi-centre, multi-national study.

Rheumatoid arthritis is one of the commonest and also the most dangerous forms of inflammatory rheumatism. Around 30% of patients achieve remission, that is to say successful control of symptoms, after just one or two years. However, despite frequent changes in treatment, many other patients have to endure the active form of the disease on an ongoing basis.

A multi-centre, multi-national study headed up by rheumatologist Daniel Aletaha of Medical University of Vienna (MedUni Vienna) as principal investigator has now shown that a new drug (sirukumab) is a very promising treatment option for these "refractory" patients.

Nowadays, treatments for rheumatoid arthritis are changed very quickly, once it is established that one is failing to effect any significant improvement. This means that many patients can be helped very quickly. On the other hand, there are patients who do not show any significant improvement even after the second or third biologic drug treatment – typically with TNF inhibitors (which blockade the Tumour Necrosis Factor TNF, which is involved in systemic inflammation). The new drug now offers a new option for such patients.

This is the result of one of the largest multi-centre, international studies so far into difficult-to-treat rheumatoid arthritis, focusing on this new mechanism of action, an interleukin-6 cytokine blockade. In this treatment, the monoclonal antibody sirukumab directly inhibits the messenger substance IL-6, which, like TNF, is responsible for inflammatory processes in the joints.

"We were able to demonstrate this in one of the largest study populations to date, with around 900 patients in 35 countries. Despite having previously received treatments with biologic drugs, these patients still had a persistently active disease. Treatment options had been practically exhausted for many of these patients. However, even in this group of patients, treatment with sirukumab brought about a significant reduction in the inflammatory action of the disease," explains Daniel Aletaha of MedUni Vienna's department of medicine III (division of rheumatology, head: Josef Smolen).

The efficacy and safety of sirukumab were tested in two different dosages (injections of 50 mg every 4 weeks or 100 mg every 2 weeks). The 100mg dosage proved to be slightly more effective. "These results are very significant in the case of a progressive, inflammatory, musculoskeletal disease such as rheumatoid arthritis, especially for those patients who are resistant to treatment," says the MedUni Vienna expert. The drug could be approved very soon.

At the same time, the new findings with sirukumab could lead to new efficacy studies being instigated for other inflammatory diseases, such as other forms of arthritis or other inflammatory diseases (vasculitis). There may also be other indications in areas other than rheumatology.

Summary
Background: Sirukumab, a human monoclonal antibody that selectively binds to the interleukin-6 cytokine with high affinity, is under development for the treatment of rheumatoid arthritis and other diseases. We aimed to assess the efficacy and safety of sirukumab for rheumatoid arthritis in a phase 3 study (SIRROUND-T).
Methods: We did a randomised, double-blind, placebo-controlled, parallel-group, multicentre study at 183 hospitals and private rheumatology clinics in 20 countries (Argentina, Australia, Austria, Belgium, Canada, France, Germany, Italy, Japan, Lithuania, Mexico, Netherlands, Poland, Portugal, Russia, South Korea, Spain, Taiwan, UK, and USA). Eligible participants were patients with active rheumatoid arthritis aged at least 18 years, with four or more of 68 tender joints and four or more of 66 swollen joints, who were refractory or intolerant to previous treatment with at least one anti-TNF drug. We randomly assigned patients (1:1:1) via a central interactive voice or web response system to either placebo every 2 weeks, 50 mg sirukumab every 4 weeks, or 100 mg sirukumab every 2 weeks, all given for 52 weeks or less. We allowed participants to continue using any concomitant disease-modifying antirheumatic drugs (DMARDs). We based the randomisation on a computer-generated, permuted-block schedule stratified by use of methotrexate at baseline (0, >0 to <12·5 mg/week, or ≥12·5 mg/week). Masking was achieved with the use of multipart labels on the study drug containers which contained directions for use and other information, but not the drug's identity. Treatments were administered by subcutaneous injection; patients assigned to 50 mg sirukumab given every 4 weeks also received a placebo injection every 2 weeks to maintain masking. At week 18, placebo-treated patients meeting early escape criteria (<20% improvement in swollen and tender joint counts) were randomly reassigned to either 50 mg or 100 mg of sirukumab. All remaining placebo-treated patients were subsequently randomly reassigned at week 24 to either sirukumab dose (crossover). The primary outcome was the proportion of patients who achieved a response of at least 20% improvement at week 16 according to American College of Rheumatology criteria (ACR20) in the intention-to-treat population (all randomly assigned participants). Safety analyses included all participants who received at least one dose (partial or complete) of study drug. This study is registered at EudraCT (number: 2010-022243-38) and ClinicalTrials.gov (number: NCT01606761).
Findings: Between July 25, 2012, and Jan 12, 2016, we randomly assigned 878 patients to treatment: 294 to placebo, 292 to 50 mg sirukumab every 4 weeks, and 292 to 100 mg sirukumab every 2 weeks. 523 (60%) of 878 patients had previously received two or more biological treatments including non-TNF drugs, and 166 (19%) of 878 were not taking a DMARD at baseline. The proportions of patients who achieved an ACR20 response at week 16 were 117 (40%) of 292 with 50 mg sirukumab every 4 weeks, and 132 (45%) of 292 with 100 mg sirukumab every 2 weeks versus 71 (24%) of 294 with placebo; differences compared with placebo were 0·16 (95% CI 0·09–0·23) for 50 mg sirukumab every 4 weeks and 0·21 (0·14–0·29) for 100 mg sirukumab every 2 weeks (both p<0·0001). Adverse event incidences in the 24-week placebo-controlled period were similar across groups (at least one event occurred for 182 patients assigned to placebo [62%, including early escape patients switched to sirukumab at week 18] of 294; 194 [66%] of 292 with 50 mg sirukumab every 4 weeks; and 207 [71%] of 292 with 100 mg sirukumab every 2 weeks). The most common adverse events in this period were injection-site erythema (four [1%] with placebo, 22 [8%] with 50 mg sirukumab every 4 weeks, and 41 [14%] with 100 mg sirukumab every 2 weeks). At week 52, of all patients receiving sirukumab including those reassigned from placebo, the most common adverse events were again injection-site erythema (33 [8%] of 416 with 50 mg sirukumab every 4 weeks and 66 [16%] of 418 with 100 mg sirukumab every 2 weeks).
Interpretation: In patients with active rheumatoid arthritis who were refractory or intolerant to anti-TNF drugs and other biological treatments, both dosing regimens of sirukumab were well tolerated and significantly improved signs and symptoms of the disease, compared with placebo, in this difficult-to-treat population.

Authors
Daniel Aletaha, Clifton O Bingham, Yoshiya Tanaka, Prasheen Agarwal, Regina Kurrasch, Paul P Tak, Sharon Popik

[link url="https://www.meduniwien.ac.at/web/en/about-us/news/detailseite/2017/news-im-februar-2017/rheumatoid-arthritis-new-treatment-option-for-difficult-to-treat-patients/"]Medical University of Vienna material[/link]
[link url="http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(17)30401-4/abstract"]The Lancet article summary[/link]

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